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- PDB-6bh5: LINKED KDM5A JMJ DOMAIN BOUND TO THE INHIBITOR 2-((2-chlorophenyl... -

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Basic information

Entry
Database: PDB / ID: 6bh5
TitleLINKED KDM5A JMJ DOMAIN BOUND TO THE INHIBITOR 2-((2-chlorophenyl)(3-(piperidin-1-yl)propoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (Compound N48)
ComponentsLysine-specific demethylase 5A, linked KDM5A JMJ domain
KeywordsOXIDOREDUCTASE/INHIBITOR / DEMETHYLASE INHIBITION / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR COMPLEX / OXIDOREDUCTASE / OXIDOREDUCTASE-INHIBITOR complex
Function / homology
Function and homology information


facultative heterochromatin formation / [histone H3]-trimethyl-L-lysine4 demethylase / histone H3K4me/H3K4me2/H3K4me3 demethylase activity / regulation of DNA-binding transcription factor activity / enzyme inhibitor activity / histone demethylase activity / Chromatin modifications during the maternal to zygotic transition (MZT) / circadian regulation of gene expression / HDMs demethylate histones / chromatin DNA binding ...facultative heterochromatin formation / [histone H3]-trimethyl-L-lysine4 demethylase / histone H3K4me/H3K4me2/H3K4me3 demethylase activity / regulation of DNA-binding transcription factor activity / enzyme inhibitor activity / histone demethylase activity / Chromatin modifications during the maternal to zygotic transition (MZT) / circadian regulation of gene expression / HDMs demethylate histones / chromatin DNA binding / histone binding / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / regulation of DNA-templated transcription / chromatin / nucleolus / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
: / : / : / : / Lysine-specific demethylase-like domain / : / PLU-1-like protein / Lysine-specific demethylase 5, C-terminal helical domain / Zinc finger, C5HC2-type / C5HC2 zinc finger ...: / : / : / : / Lysine-specific demethylase-like domain / : / PLU-1-like protein / Lysine-specific demethylase 5, C-terminal helical domain / Zinc finger, C5HC2-type / C5HC2 zinc finger / ARID DNA-binding domain / ARID DNA-binding domain superfamily / ARID/BRIGHT DNA binding domain / ARID domain profile. / BRIGHT, ARID (A/T-rich interaction domain) domain / ARID/BRIGHT DNA binding domain / JmjN domain / jmjN domain / JmjN domain profile. / Small domain found in the jumonji family of transcription factors / Cupin / JmjC domain, hydroxylase / A domain family that is part of the cupin metalloenzyme superfamily. / JmjC domain / JmjC domain profile. / Zinc finger, PHD-type, conserved site / PHD-finger / Zinc finger PHD-type signature. / Zinc finger PHD-type profile. / Zinc finger, PHD-finger / Zinc finger, PHD-type / PHD zinc finger / Zinc finger, FYVE/PHD-type / Zinc finger, RING/FYVE/PHD-type / Jelly Rolls / Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-DNY / : / Lysine-specific demethylase 5A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.651 Å
AuthorsHorton, J.R. / Cheng, X.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM049245-23 United States
Citation
Journal: J. Med. Chem. / Year: 2018
Title: Insights into the Action of Inhibitor Enantiomers against Histone Lysine Demethylase 5A.
Authors: Horton, J.R. / Liu, X. / Wu, L. / Zhang, K. / Shanks, J. / Zhang, X. / Rai, G. / Mott, B.T. / Jansen, D.J. / Kales, S.C. / Henderson, M.J. / Pohida, K. / Fang, Y. / Hu, X. / Jadhav, A. / ...Authors: Horton, J.R. / Liu, X. / Wu, L. / Zhang, K. / Shanks, J. / Zhang, X. / Rai, G. / Mott, B.T. / Jansen, D.J. / Kales, S.C. / Henderson, M.J. / Pohida, K. / Fang, Y. / Hu, X. / Jadhav, A. / Maloney, D.J. / Hall, M.D. / Simeonov, A. / Fu, H. / Vertino, P.M. / Yan, Q. / Cheng, X.
#1: Journal: Cell Chem Biol / Year: 2016
Title: Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds.
Authors: Horton, J.R. / Liu, X. / Gale, M. / Wu, L. / Shanks, J.R. / Zhang, X. / Webber, P.J. / Bell, J.S. / Kales, S.C. / Mott, B.T. / Rai, G. / Jansen, D.J. / Henderson, M.J. / Urban, D.J. / Hall, ...Authors: Horton, J.R. / Liu, X. / Gale, M. / Wu, L. / Shanks, J.R. / Zhang, X. / Webber, P.J. / Bell, J.S. / Kales, S.C. / Mott, B.T. / Rai, G. / Jansen, D.J. / Henderson, M.J. / Urban, D.J. / Hall, M.D. / Simeonov, A. / Maloney, D.J. / Johns, M.A. / Fu, H. / Jadhav, A. / Vertino, P.M. / Yan, Q. / Cheng, X.
#2: Journal: J. Biol. Chem. / Year: 2016
Title: Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases.
Authors: Horton, J.R. / Engstrom, A. / Zoeller, E.L. / Liu, X. / Shanks, J.R. / Zhang, X. / Johns, M.A. / Vertino, P.M. / Fu, H. / Cheng, X.
History
DepositionOct 29, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 28, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 25, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Lysine-specific demethylase 5A, linked KDM5A JMJ domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8309
Polymers37,9451
Non-polymers8858
Water4,252236
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1200 Å2
ΔGint2 kcal/mol
Surface area13610 Å2
Unit cell
Length a, b, c (Å)116.370, 61.843, 46.704
Angle α, β, γ (deg.)90.00, 92.35, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-883-

HOH

21A-910-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Lysine-specific demethylase 5A, linked KDM5A JMJ domain / Histone demethylase JARID1A / Jumonji/ARID domain-containing protein 1A / Retinoblastoma-binding ...Histone demethylase JARID1A / Jumonji/ARID domain-containing protein 1A / Retinoblastoma-binding protein 2 / RBBP-2


Mass: 37944.836 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDM5A, JARID1A, RBBP2, RBP2 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): Gold C-plus
References: UniProt: P29375, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With 2-oxoglutarate as one donor, and incorporation of one atom of oxygen into each donor

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Non-polymers , 5 types, 244 molecules

#2: Chemical ChemComp-DNY / 2-{(S)-(2-chlorophenyl)[3-(piperidin-1-yl)propoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid


Mass: 427.924 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26ClN3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mn
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 236 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.21 Å3/Da / Density % sol: 44.41 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop
Details: 1.2-1.35 M (NH4)2SO4, 0.1 M Tris-HCl (pH 8.6-9.2), 0-20% glycerol, 25 mM (Na/K) dibasic/monobasic phosphate
PH range: 8.6-9.2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 13, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.65→32.841 Å / Num. obs: 39298 / % possible obs: 98.7 % / Redundancy: 4.8 % / Rmerge(I) obs: 0.062 / Rpim(I) all: 0.031 / Net I/σ(I): 22
Reflection shellResolution: 1.65→1.71 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.501 / Mean I/σ(I) obs: 2 / Num. unique obs: 3505 / CC1/2: 0.78 / Rpim(I) all: 0.293 / % possible all: 89

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Processing

Software
NameVersionClassification
PHENIXdev_2863refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5E6H

5e6h


Resolution: 1.651→32.841 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 22.72
RfactorNum. reflection% reflection
Rfree0.216 1990 5.07 %
Rwork0.1952 --
obs0.1963 39287 98.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.651→32.841 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2312 0 57 236 2605
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022484
X-RAY DIFFRACTIONf_angle_d0.4663392
X-RAY DIFFRACTIONf_dihedral_angle_d13.3331449
X-RAY DIFFRACTIONf_chiral_restr0.042347
X-RAY DIFFRACTIONf_plane_restr0.004443
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6512-1.69250.36911240.30292319X-RAY DIFFRACTION87
1.6925-1.73820.27041460.27342564X-RAY DIFFRACTION95
1.7382-1.78940.2561500.25662641X-RAY DIFFRACTION99
1.7894-1.84710.26931370.24032695X-RAY DIFFRACTION100
1.8471-1.91310.26241280.23742670X-RAY DIFFRACTION100
1.9131-1.98970.21581640.21322700X-RAY DIFFRACTION100
1.9897-2.08030.21591320.20122689X-RAY DIFFRACTION100
2.0803-2.18990.22981620.19892677X-RAY DIFFRACTION100
2.1899-2.32710.23011320.19732714X-RAY DIFFRACTION100
2.3271-2.50670.21931410.20112694X-RAY DIFFRACTION100
2.5067-2.75880.23931390.2042729X-RAY DIFFRACTION100
2.7588-3.15780.22161420.18882706X-RAY DIFFRACTION100
3.1578-3.97740.18431460.16752714X-RAY DIFFRACTION100
3.9774-32.84750.17991470.16862785X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.80330.59460.22511.94010.67361.42680.00190.0417-0.19690.0870.0997-0.26910.15250.3305-0.10040.19450.0217-0.02790.21440.01120.2244-14.734.65296.4361
21.29180.4996-0.08052.68640.17062.7612-0.02-0.09220.08170.2676-0.01920.1443-0.1047-0.1850.03730.19340.01940.020.1618-0.01530.1568-30.581222.624819.1969
31.8271-0.1199-0.5180.8408-0.27221.04140.08210.16350.6263-0.0540.0726-0.3946-0.28720.3274-0.120.2672-0.09790.04290.2979-0.05540.3608-11.499526.73529.8792
41.8134-0.3765-0.41183.48150.47021.41380.15490.06250.1163-0.14360.1264-0.0126-0.22680.3991-0.25070.159-0.0460.05440.334-0.01830.2591-5.153117.36212.3087
50.83570.08880.14560.73220.58480.7735-0.02520.01620.04930.00480.01670.0112-0.14840.0560.01240.1751-0.0082-0.00980.14430.01340.1379-23.013216.62896.571
60.5492-0.05330.19740.9078-0.07970.6990.06560.0689-0.0013-0.1333-0.10460.22-0.0398-0.23430.02970.23030.01090.00750.2559-0.02730.2685-38.383914.9854-1.9472
70.99660.14430.02551.43370.63671.526-0.01270.0231-0.0462-0.00910.0075-0.03540.05950.03540.01080.16130.0013-0.00750.13720.01310.1407-22.889912.06626.0545
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 12 through 62 )
2X-RAY DIFFRACTION2chain 'A' and (resid 63 through 405 )
3X-RAY DIFFRACTION3chain 'A' and (resid 406 through 432 )
4X-RAY DIFFRACTION4chain 'A' and (resid 433 through 469 )
5X-RAY DIFFRACTION5chain 'A' and (resid 470 through 507 )
6X-RAY DIFFRACTION6chain 'A' and (resid 508 through 547 )
7X-RAY DIFFRACTION7chain 'A' and (resid 548 through 588 )

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